Rational treatment of respiratory disease, especially acute respiratory failure and CO2 retention in chronic diseases, is based on the understanding of CO2 control of breathing. The medullary chemoreceptors play a crucial role in regulating breathing but the mechanisms governing their activity are not established. The relation between hydrogen ion activity in medullary chemoreceptor tissue and phrenic nerve activity will be studied in anesthetized rats and cats by measuring tissue pH with a pH microelectrode during changes of arterial PCO2 and PO2. The possibility of trans-arteriolar CO2 exchange during high flow CSF perfusion will be tested by measuring tissue pH while changing arterial and CSF perfusate PCO2 in the same and in opposing directions. By measuring local tissue perfusion with a servo controlled temperature probe, with simultaneous measure of tissue pH, the response of blood flow in the chemoreceptor tissue to changes of PO2 and PCO2 and its relation to tissue hydrogen ion activity will be studied. The effect on tissue pH of the carrier mediated exchange of HCO3- across cells will be studied by measuring tissue pH response to altering arterial PCO2 before and after pharmacologic block of the HCO3 carrier. Yamamoto's hypotheses concerning the generation of CO2 by respiratory neuron activity and consequent chemoreceptor stimulation will be tested by measuring chemoreceptor pH during stimulation of the carotid sinus nerves. These studies should provide evidence to reject or accept hypotheses of chemoreceptor mechanisms which are of cardinal importance.